The long-term goal of the candidate's research program is to understand the biological basis for clinical heterogeneity in Alzheimer's disease in an effort to clarify the etiology(ies) of this disorder and its behavioral complications. This central theme is being pursued under the auspices of two ongoing NAMH-funded research grants. The first of these focuses on the clinical biology of a genetic factor that modifies the clinical expression of AD and whose segregation can be assessed through its effects on platelet membrane fluidity. The second approach employs a clinicopathological study of the brain morphological and neurochemical correlates of major depression in the context of AD. In addition, the candidate proposes incorporate APOE genotyping into the prospective longitudinal study of the AD high-risk cohort and ongoing genetic studies of the PME locus. Finally, the Candidate section provides a perspective on several innovative experimental approaches and methods that are in various stages of development in the candidate's laboratory.